JPS63260575A - Portable permeable injection apparatus controlled in release of drug - Google Patents

Abstract

A portable controlled release osmotic infusion device, which can be activated on demand by the user, comprises a rigid housing (6) containing: (a). a fluid-imbibing assembly, comprising a solvent-containing chamber (7) and a solute-containing chamber (8); the two chambers (7, 8) separated by a rigid semipermeable membrane (12) covered by a thin taut foil seal (5), (b). a drug-containing chamber (10) separated from the fluid-imbibing assembly by a leakproof impermeable elastic diaphragm (9), which expands into the drug-containing chamber (10) in use and drives the drug through a dispensing orifice (1) at a steady rate, and (c). an activating device (4) which ruptures the foil seal (5) described in (a) above and initiates the osmotic action of the device. The osmotic device is filled with drug in solution or suspended form during manufacture and can be stored without deterioration of the contents for prolonged periods of time.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to an infusion device.
), and particularly relates to a portable infusion device that can be held inside or outside the body by a user, and that further controls the release of the drug so that the drug can be constantly administered over a long period of time.

BACKGROUND OF THE INVENTION Various drug treatments require continuous drug delivery rather than single or multiple injections. Advantages of continuous therapy include, for example, reduced toxicity and other side effects of acute drug administration, significantly improved therapeutic efficacy, and increased comfort for the patient.

The traditional method of providing continuous oral therapy is intravenous infusion. Although this method is possible in hospitals, it is clear that it severely limits the activities of the patients being treated. Therefore, in the past few years there has been a lot of research into developing small, portable infusion pumps. The simplest such pump uses a mechanical or battery-powered motor to drive a syringe or an agitation motor, which is secured to the user by a fitting. A typical example is the “Portable Heparin Syringe” by A. J. Handley.
1njector) J(The Lancet,
2.313 (1970)). A recent development in the field is the implantable minitinia pump. this .

This type of pump was developed especially for the treatment of diabetes by continuous insulin administration, and in addition to the affective or cylinder device, it also incorporates other elements, such as the elastic tension of a sound-tensioned rubber balloon or the liquid pump. It is added by the vapor pressure of the propellant. A review of these pumps can be found in M, V, 5ef
“Implantab Pump” by ton
le Pumps) J (Medical Appl
cations of Controlled R
e1ease Vat, 1. .

Edited by R, S, Langer, and L, Wise, CR3.
Press, Boca Raton.

PL (1984)).

The disadvantage of such pumps is that they are very complex and expensive to manufacture, making them unsuitable for widespread use. Moreover, many of them are designed to deliver relatively large amounts of liquid, several mI! It is not intended to supply small quantities such as would be valid on the order of .

On the other hand, Ros Nelson (Ros Nelson) as detailed below
Small osmotic pumps based on the principle of the e-Nelson pump have also been devised.

The pump works by imbibition of water from conditions in the surrounding environment and is designed to be implanted or ingested into the body, so absorption of bodily fluids is the triggering mechanism. ing. A typical example is the American name A by F. Theeuwes.
lza (Pa1o Alto, California, USA)
) can be obtained commercially. Theeuwes also developed a further simplification of the Rose-Nelson principle that could be manufactured from a simple tablet machine (U.S. Pat. No. 3.845, issued November 1974).
No. 770). These mini osmotic pumps and tablets
It has the ability to deliver doses of drug on the order of mβ at dosing rates on the order of IUβ/hour.

Although these devices are easy and inexpensive to manufacture,
Because of the need to be under aqueous conditions, they are generally limited to intracorporeal use.

The advantages of the Rose-Nelson type device of being simple, reliable, and compact have not been fully exploited in osmotic pumps intended for somatic use. U.S. Patent Nos. 3 and 6
No. 04,417 (September 1971) discloses an improvement to the Rose Nelson pump that uses an elastic diaphragm instead of a moving piston to separate the drug chamber and base, so that both drug and salt are in solution. It is now loaded as. U.S. Pat. No. 4,474,048 further states:

Another improvement is disclosed in which an impermeable elastic wall is used and a movable end wall is rotated to provide pulsed delivery of the contained drug at any time during pump operation. There is. Additionally, U.S. Patent No. 4.474,5
No. 75 relates to a modification of the device of U.S. Pat. No. 4,474,048 in which the flow rate of the dispersed drug is varied by varying the area of the semipermeable membrane exposed to the ice chamber.

US Pat. No. 4,552,561 discloses a pump device for use in small osmotic pumps, which device can be loaded with the drug to be administered prior to use. Operation of the pump is initiated by filling the lower chamber of the housing with hydrogel. If the pump works,
Pulse administration of drug is achieved using any mechanism.

All of the above-mentioned patents disclose pumps that are self-driven and begin operating as soon as the contents of each chamber are loaded. However, it is often desirable to load the pump and store the pump until needed. In this way, the pump can be manually installed at a pharmacy, and there is no need to install it at a hospital, for example. Moreover, if the loaded pump could be stored, supplied to potential users, and activated as needed, the field of application would be very wide, for example in the field of toxic attacks on the battlefield, or in severe It will also be possible to use it in cases where medical emergencies such as allergic reactions are required.

PROBLEM SOLVED BY THE INVENTION Thus, a primary object of the present invention is to provide a portable osmotic infusion pump with controlled drug release that can be activated quickly and easily as needed.
sion pump).

Another object of the present invention is to provide a pump that can be stored containing medication and pump hydraulic fluid for extended periods of time without deterioration of performance.

Yet another object of the present invention is to provide such a pump that is inexpensive and easy to manufacture.

Other objects and advantages of the present invention will become apparent from the following description and practice of the invention. The objects and advantages may be obtained by means of the devices and features or combinations thereof particularly pointed out in the claims.

Means for Solving the Problems In order to achieve the above-mentioned object, according to the present invention, 195
Rose and Nelson in the 00s
A portable osmotic infusion pump with controlled drug release is provided based on the principle of an osmotic pump originally devised by John S., Rose and Nelson, J. F.
-TermInjector)”, Au5tral,
J, exp Biol, pp. 33.415-420 (
1955)). The Rose-Nelson pump consists of three chambers: a base chamber containing excess solid salt, a drug chamber, and an ice chamber. The base and ice chamber are separated by a rigid membrane that is permeable to water but impermeable to salt. The base and drug chambers are separated by a rubber diaphragm. When the device is operated, water is osmotically imbibed into the base, which causes the rubber diaphragm to expand into the drug chamber and force the drug through the delivery orifice. Depending on the salt used, the osmotic pressure generated by this type of pump is usually between 50 and 200 atmospheres. Since the pressure required to pump the drug out of the device is relatively low, the rate of drug release (feed rate) is constant as long as there is excess undissolved salt remaining in the base.

The portable infusion pump disclosed by the present invention includes a fluid-imbibing ass.
assembly) and a drug chamber, and further includes an actuation mechanism (
octiratormechanism). This outer housing can be made of metal or plastic, for example, and is typically manufactured using conventional mass production techniques. The permeate absorbing member is composed of a solvent-containing chamber and a solute-containing chamber, which are separated by a rigid semipermeable membrane. This membrane is
Separated from the solvent chamber by a thin foil seal, the seal is
Stainless steel washers keep it tight and taut. When the foil (seal) is destroyed, the porous core (w
ick) absorbs the osmotic fluid and brings it into contact with the membrane, and the osmotic pump action is initiated.

Preferred osmotic fluid (osmotic fl
uid) is water, and as used herein, the permeate is generally referred to as water, and the chamber in which the fluid is originally contained is referred to as an ice chamber. However, other fluids may be preferred, and the invention encompasses any combination of solute, solvent, and semipermeable membrane that provides osmotic power to the pump.

The actuation mechanism consists, for example, of a simple plunger and needle, which functions by piercing the foil seal. However, the mechanism of operation of the pond is also possible and will be detailed below. Accordingly, the present invention encompasses any actuation mechanism.

The combination of solute, solvent and membrane is selected depending on the desired flow properties. The drug-containing chamber is separated from the permeate-absorbing member by an elastic diaphragm, which differs from existing conventional diaphragms in that it is more impermeable. Standard elastomers such as latex rubber, butyl rubber or styrene/butadiene copolymers are not sufficient to prevent migration of the contents of the chamber into the base over long periods of time. It is clear that such movement is undesirable when the pump is used as a simple off-the-shelf device that can be actuated by the user.

The foregoing general description and the following detailed description are intended to be illustrative and not limiting.

The term "drug" used in the present invention refers to a physiological or pharmacological drug that has a local effect at the site of administration or a systemic effect at a site remote from the site of administration. Refers to all active substances.

The above-mentioned purpose was established in 1955 by Rose
) and by a device based on the osmotic pump system first proposed by Nelson et al.

Referring to the drawings, FIG. 1 shows a basic embodiment of the invention. The outer housing 6 must be rigid and non-irritating to the skin, and must also be composed of a material that is non-reactive and impermeable to the contained salts, solutions and drugs. Biologically compatible when intended for implantation
ible). Furthermore, the material selected is preferably one that is inexpensive and can be reliably mass-produced. Typical materials that can be used include, for example, stainless steel, aluminum, polyolefin, polycarbonate, and the like. A hole is preferably machined into the top surface of the housing, and the hole is closed with a hydrophobic, air permeable material such as porous Teflon to form a water chamber 7. The water is discharged without reducing the pressure. In selecting the material of the bottom plate 11, similar criteria as mentioned above apply. If desired, the outer surface of the plate may be adhesive to facilitate retention of the pump in place on the body.

The actuating mechanism (actuator) shown in FIG. 1 is a plunger and a needle. Pumping is initiated by removing the protective spacer 3 and pressing the raised button of the plunger on the top of the device.

The pressure thus applied causes the plunger 4 to puncture the foil seal 5. If desired, an injection needle may be coupled to the actuating plunger so that pressing the plunger forces the injection needle into the skin.

Additionally, this type of actuation mechanism allows for an initial small dose of active agent or drug to be administered to the user when the button is pressed. Alternatively, standard commercially available subcutaneous drug administration devices 1 such as Travenol Labo
Ratories. When the flake seal is broken, the porous wick 13 draws water from the water chamber 7 by capillary action into contact with the semipermeable membrane 12. The water then seeps into the base (salt chamber: 5 alt Chamber) due to osmotic pressure.

The elastic diaphragm 9 expands into the medicament chamber 10 and forces the medicament through the dosing port 1 to reach the injection or administration site.

Several alternative examples of actuation mechanisms are illustrated in the second leapfrog, FIGS. 3, 4, and 5. FIG. 2 shows a drilling mechanism similar to the embodiment described above. The plunger is
The needle has a dollar-shaped protrusion 19 extending inside the water chamber. The flake seal 5 is held taut by a rigid support plate 2. The plate further includes:
It also has the function of reinforcing the semipermeable membrane 12 to prevent it from being pushed into the ice chamber by the osmotic pressure of the salt solution during operation of the pump. When the plunger is pressed, the needle 19 pierces the flake seal, allowing water to contact the porous wick 13. The pump then operates as described above. In the arrangement shown in FIG. 3, a seal (usually aluminum foil) separating the ice chamber from the wick is bonded by epoxy adhesive 14 to a rotatable dial 15 at the top of the pump. When the dial is turned, the foil (seal)
is torn and the pump operation as described above begins. Such a mechanism may be preferred in that it provides a larger opening from the ice chamber to the wick and therefore provides a faster response time than perforated devices. Additionally, there is the advantage of eliminating needles that can damage the membrane. 4th A
The figure illustrates a mechanism including a rubber septum 16 and a hollow needle 20. When the plunger is pressed, the needle pierces the septum, allowing water to flow and contact the wick (
4B), pump operation is initiated as described above. FIG. 5A shows yet another embodiment using valve 21. FIG. During storage, the valve is in the closed position as shown on the left in Figure 5B. To operate the pump, the dial is rotated 180°, so that the fifth
The valve is fully open as shown on the right side of Figure B.

Water thus comes into contact with the wick, as in the previous case.

It will be appreciated that various mechanisms may be used to operate the pump and are not limited to the techniques described above.

In FIG. 6, a typical behavior of the pump in the example of FIG. 1 is shown graphically. The operating speed of the pump (pump speed) depends on the membrane and salt employed. The pump operating rate at steady state is given by dv Ak π dt n , where dv/dt is the outflow volume of drug from the pump and is equal to the inflow volume of water into the base;
A is the area of the membrane, and k is the permeation rate of water through the membrane, expressed as cat-c[I+/caf-atm-hr, ! is the membrane thickness and π is the osmotic pressure of the saturated salt solution in the base. Thus, selecting a suitable membrane material is important for good pump behavior.

A preferred choice is one of the esters or ethers of cellulose, such as cellulose acetate and cellulose butyrate. Cellulose acetate is particularly preferred because it has a long history of use as a membrane and is easy to form into reproducibly thin membranes using standard solution methods.

The osmotic pressure of the saturated salt solution must be greater than the pressure required to pump the drug out of the device, and the amount of salt used must be such that no excess solid salt is present during the life of the pump. must be in such an amount that it remains. By doing so, a constant drug supply rate can be ensured throughout the period of use.

Furthermore, as can be seen from FIG. 6, the pump stops immediately when the contents of the icebox are emptied. This is a particular advantage of the pump according to the invention.

That is, as long as the volume of the ice compartment is smaller than the volume of the drug compartment, there is no risk that the osmotic pressure will be high enough to destroy the diaphragm and cause the salt solution to be pumped out to the user. The osmolality of a saturated salt solution depends on the molecular weight and solubility of the iron salt, and for many common salts it ranges from 50 to 20
It is in the range of 0 atmospheric pressure. A wide variety of suitable solutes are disclosed in US Pat. No. 4,034,756, which is incorporated by reference. Preferred salts are sodium chloride, potassium chloride, magnesium sulfate and sodium sulfate. These salts allow a good range of osmotic pressure differences across the membrane and allow the pump flow rate to be varied depending on the desired application. Another advantage of osmotic pumps is that the pressure at which they operate is sufficiently high to overcome pressure delivery such as that caused by blockage of the delivery needle. This type of occlusion is often a source of trouble in other types of small infusion pumps.

A feature of the infusion device of the present invention is that it can be stored for a long period of time in a loaded state and activated when needed, so the expansible elastic diaphragm must be completely impermeable to the drug. It is important not to Otherwise, fluid from the drug chamber will gradually migrate into the base and spoil the device during storage. A wide range of standard non-permeable materials with good elastic properties are known in the art, including latex rubber, polyisoprene, butyl rubber, nitrile rubber, styrene/butadiene copolymers, and the like. However, these materials are not suitable when storage periods of months or even years are intended. An alternative preferred material is a standard elastomer laminated with a thin layer of aluminum foil, which breaks as soon as the elastic diaphragm begins to expand. Next preferred are metallized elastomeric materials obtained by vacuum deposition of aluminum or carbon metal onto elastomeric rubber-based materials.

Examples of the contents of the drug chamber are a single drug or a combination of drugs, typically administered parenterally. A preferred embodiment is the drug dissolved or suspended in a suitable solvent (generally water). Another preferred embodiment is a lyophilized drug, which is particularly preferred when the stability of the drug to be used in solution is limited. In this case, just before dispensing, water would be added to the chamber by the pharmacist by injection through a small septum in the wall of the chamber. Agents used in such methods include, but are not limited to, protein and polypeptide drugs such as insulin, growth hormone, interferon, interleukin-2, and LHRH.

If desired, - any of the devices as previously exemplified may be equipped with the ability to perform an initial dose to provide a rapid initial treatment, followed by a gradual controlled release of the drug over an extended period of time; You can also make it possible. There are various ways to achieve this goal. A typical method is illustrated in FIG. 9, which provides an understanding of the principle.

FIG. 9 shows the basic embodiment of FIG. 1 with the addition of an initial dosing mechanism 18, which is located within the outer casing 22 adjacent to the osmotic pump 17.
(See plan view in Figure 9A).

As can be seen from FIG. 9B, the initial dispensing mechanism is in contact with the second drug chamber 23. Activation of the initial dispensing mechanism reduces the volume of the second medicament chamber and delivers a corresponding volume of medicament to the user.

The initial dosing mechanism can be actuated using a screw. That is, when the part protruding from the outer casing is rotated, the initial dosing mechanism is rotated into the casing and
Decreasing the volume of the second drug chamber. Alternatively, it may take the form of a spring-loaded plunger, slide valve, piston, or the like. After this initial dose, the osmotic action of the pump begins, resulting in a gradual, controlled release of the drug.

The invention can also be used as a portable injection device. That is, it can be used in medical fields that cannot be applied with current technology. For example, it can be applied in emergency cases where a severe allergic reaction occurs.

Patients with pre-existing allergic symptoms can keep a pre-treated device of the invention and use it as needed. Another preferred use is the administration of antidotes. DTI
C Report “υ, S, Army Chemical
Effects Data Requirements
(MON^-WE-1-82 (1982)) reports that current antidotes to chemical weapons are unsatisfactory. Some of the new antidotes under development: 1
Although controlled gradual delivery over a period of 1 to 3 days is required, the present invention provides a new solution to controlled drug administration therapy in the field. That is, the device of the present invention can be stored in a preloaded state for months or even years and given to military personnel prior to combat. Existing portable injection devices could not be used in this manner. Additionally, the pump of the present invention can be used in long-term leprosy treatment, infectious disease treatment, or other medical fields where portable infusion devices are utilized.

EXAMPLES In order to further clarify the characteristics of the present invention, Examples will be shown below, but these Examples are merely illustrative and do not limit the scope of the present invention.

Example 1: The apparatus of the present invention shown in FIG. 1 was manufactured. The body of the pump was machined from aluminum. The pump has a thickness of 130m
, had a diameter of 3.5 am, and weighed 6.9 grams. The semipermeable membrane used was acetic acid acetate with a thickness of 50 microns.
98.10 (manufactured by Eastman Kodak, Inc., ingsport, Tennessee, USA) was poured onto a clean glass plate. The permeating salt employed was sodium chloride, and water was used as the working fluid. The elastic diaphragm was made of latex rubber layered on a thin disc of aluminum foil. The behavior of the pump is shown in the graph of FIG.

Immediately after actuation, there is a large initial drug release, after which the pump reaches steady state and the pump rate remains at 1. On+j'/day. The pump stopped as soon as the ice chamber was depleted, but at this time some drug solution remained in the drug chamber.

Example 2: A device was fabricated according to the method described in Example 1. Semipermeable membranes of various thicknesses (all made of cellulose acetate) were used. The obtained results are shown in the graph of FIG. As shown in FIG. 3, the pump speed was found to be dependent on the membrane thickness. Thus, by varying the membrane thickness, the pump can be designed to provide a specific drug delivery rate.

Example 3: A device was fabricated as in Example 1 using a cellulose acetate membrane (15 microns thick). Four different types of osmotic salts were used, but in all cases the working liquid (osmotic liquid) was water. The results are summarized in Table 1 below.

From this result, it is understood that the feed rate of the pump can be adjusted by selecting an appropriate salt.

Example 4: An injection device was produced in the same manner as in Example 1, but a dial as shown in FIG. 3 was used as the operating mechanism. When I turned the dial, the foil tore open and the pump activated. The opening from the ice chamber to the wick was larger than with perforated operation. As a result, the time delay until pumping action begins was significantly reduced.

Example 5: An injection device was produced in the same manner as in Example 1, and the drug chamber was filled with aqueous glycerin solutions of various viscosities. The results are shown in Table 2.

The viscosity of the glycerin solution in Table 2 changed by more than 100 times,
The change in pump speed is less than 15%.

As expected theoretically, the pump speed was essentially independent of the viscosity of the drug solution.

Various modifications, variations, and improvements can be made to the present invention as described above, and these are also included within the scope of the present invention.

[Brief explanation of the drawing]

FIG. 1 is a sectional view showing a basic embodiment of the present invention. FIG. 2 illustrates an embodiment of the invention operated by a drilling mechanism. FIG. 3 illustrates an embodiment of the invention operated by a tearing mechanism. FIG. 4A illustrates an embodiment of the invention operated by a septum/perforated hollow needle. FIG. 4B is an enlarged view of the septum/piercing needle of FIG. 4A. FIG. 5A illustrates an embodiment of the invention that is actuated by a valve. , FIG. 5B is the same as FIG. 5A.
FIG. 3 is an enlarged view of the actuated valve shown in FIG. FIG. 6 is a graph showing the pump action in the device of FIG. 1. FIG. 7 is a graph showing the pump action when the thickness of the semipermeable membrane is changed in the device of FIG. 1. FIG. 8 is a graph showing the relationship between pump speed and membrane thickness. FIG. 9A is a plan view of an embodiment of the invention with a device for initial administration of a drug. FIG. 9B is a cross-sectional view of the embodiment shown in FIG. 9A.・ 5... Seal, 6... Housing, 7... Ice chamber (solvent containing chamber), Death... Base (solute containing chamber), 9... ... Elastic diaphragm, 10 ... Drug chamber (drug containing chamber), 12 ... Semipermeable membrane, 13.
... Porous core, 4.5.14.15.19.20.
...Operating mechanism. Name of the invention: Portable osmotic injection device with controlled drug release 3, Relationship to the amended person's case Applicant's name: Pharmatrix Corporation 4,
agent

Claims (11)

[Claims] (1) A portable osmotic injection device loaded with a drug and an osmotic fluid, which can be stored for a long period of time without deterioration, and which has controlled drug release and can be activated by the user when necessary, (a) Housing; (b) consisting of a solvent-containing chamber and a solute-containing chamber;
(c) a permeate absorbing member such that the two chambers are separated by a rigid semi-permeable membrane which is protected from the solvent by a seal during storage; a drug-containing chamber separate from the permeate-absorbing member, the diaphragm being adapted to expand into the drug-containing chamber in use and release the drug at a constant rate through a delivery orifice; (d) An injection device comprising an actuation mechanism that breaks the seal between the semipermeable membrane and the solvent to initiate a pumping action. (2) The device according to claim (1), wherein the seal that protects the semipermeable membrane is a metal foil, and the actuating mechanism is a perforation device that perforates the seal. (3) The device according to claim (1), wherein the seal protecting the semipermeable membrane is a metal foil, and the actuating mechanism is adapted to tear the seal. (4) The device according to claim (1), wherein the seal that protects the semipermeable membrane is a diaphragm, and the actuation mechanism is a hollow needle that pierces the diaphragm. 5. The device of claim 1, wherein the seal protecting the semipermeable membrane includes a valve, and the actuation mechanism is adapted to open the valve. (6) A device according to claim 1, wherein the elastic diaphragm is covered with a layer of metal foil. (7) The device according to claim (1), wherein the elastic diaphragm is covered with a vacuum-deposited metal film. (8) The device according to claim (1), wherein the drug is an antidote for a toxic substance. (9) the drug is in a freeze-dried solid form during storage;
A device according to claim 1, wherein the device is adapted to be returned to its original state before it is put into operation. (10) Claim No. 1 in which the drug is a polypeptide (
The device described in item 1). (11) (a) a second drug-containing chamber that is separated from but connected to the drug-containing chamber; and (b) means for reducing the volume of the second drug-containing chamber. The apparatus according to claim 1, further comprising: